C-protected Amino Acids Research Articles

Synthesis, in vitro evaluation and molecular docking studies of novel naphthoisoxazolequinone carboxamide hybrids as potential antitumor agents

Based on previous results with benzoindazolequinone (BIZQ) derivatives, a new series of bioisosteric 3-methylnaphtho[2,3-d]isoxazole-4,9-quinones (NIQs), conjugated with C-protected amino acids as glycine (Gly), L-alanine (Ala), L-phenylalanine (Phe) and L-glutamic acid, were synthesized from NIQ 2, and the chemical structures of intermediates and hybrids were elucidated by spectroscopic techniques. The antiproliferative activity of NIQs was evaluated by in vitro assay on cultured MCF-7 breast adenocarcinoma and KATO III gastric carcinoma cells. All the compounds showed to be cytotoxic against both cell lines, with IC50 values between 22.9 and 215.3 µM. NIQ hybrids 6, 8, and 9, conjugated with Gly, Phe and Glu, respectively, showed to be more cytotoxic, and hybrid 8 also proved to have higher activity than the precursor 2 against MCF-7 cells. Docking studies showed that NIQs exhibited very good binding energies (ΔG bin ) in the active site of proteins that participate in key carcinogenic pathways.

Reaction of Amino Acids, Di- and Tripeptides with the Environmental Oxidant NO3. : A Laser Flash Photolysis and Computational Study.

Absolute rate coefficients for the reaction between the important environmental free radical oxidant NO3. and a series of N- and C-protected amino acids, di- and tripeptides were determined using 355 nm laser flash photolysis of cerium(IV) ammonium nitrate in the presence of the respective substrates in acetonitrile at 298±1 K. Through combination with computational studies it was revealed that the reaction with acyclic aliphatic amino acids proceeds through hydrogen abstraction from the α-carbon, which is associated with a rate coefficient of about 1.8×106 m-1 s-1 per abstractable hydrogen atom. The considerably faster reaction with phenylalanine [k=(1.1±0.1)×107 m-1 s-1 ] is indicative for a mechanism involving electron transfer. An unprecedented amplification of the rate coefficient by a factor of 7-20 was found with di- and tripeptides that contain more than one phenylalanine residue. This suggests a synergistic effect between two aromatic rings in close vicinity, which makes such peptide sequences highly vulnerable to oxidative damage by this major environmental pollutant.

Fe-amino acid complexes immobilized on silica gel as active and highly selective catalysts in cyclohexene epoxidation

In this work, the syntheses, structure, superoxide dismutase (SOD) activity, and the catalytic use in the oxidative transformations of cyclohexene of covalently grafted Fe(III)-complexes formed with various or various combinations of C-protected amino acid (l-histidine, l-tyrosine, l-cysteine and l-cystine) ligands are presented. The structural features of the surface complexes were studied by XANES/EXAFS and mid/far-IR spectroscopies. The compositions of the complexes were determined by ICP-MS and the Kjeldahl method. The SOD activities of the materials were evaluated in a biochemical test reaction. The obtained materials were used as catalysts for the oxidation of cyclohexene with peracetic acid in acetone. Both covalent grafting and building the complex onto the surface of the chloropropylated silica gel were successful in most cases. In many instances, the obtained structures and the coordinating groups were found to substantially vary upon changing the conditions of the syntheses. All the covalently immobilized Fe(III)-complexes displayed SOD activities, and most of them were found to be capable of catalyzing the oxidation of cyclohexene with appreciably high activities and outstanding epoxide selectivities.

Building, characterising and catalytic activity testing of Co–C-protected amino acid complexes covalently grafted onto chloropropylated silica gel

Co–C-protected amino acid (C-protected L-histidine, L-tyrosine, L-cysteine and L-cystine) complexes were covalently grafted onto chloropropylated silica gel, and the materials thus obtained were structurally characterised by mid/far IR and X-ray absorption spectroscopies. The superoxide dismutase-like activities of the substances were determined via the Beauchamp–Fridovich test reaction. It was found that covalent grafting and the preparation of the anchored complexes were successful in most cases. The coordinating groups varied upon changing the conditions of the syntheses. All materials displayed catalytic activity, although catalytic activities differed widely.

Superoxide dismutase inspired immobilised Ni(II)–protected amino acid catalysts—Synthesis, characterisation, and catalytic activity

Covalently anchored Ni(II)–C-protected amino acid (l-histidine, l-cysteine, and l-cystine) complexes inspired by the active site of the Ni-superoxide dismutase enzyme were synthesised using chloropropylated silica gel as support. The structural features of the surface complexes were studied by the Kjeldahl method and ICP-MS, mid/far IR, UV–vis diffuse reflectance, and X-ray absorption spectroscopies. The enzyme-like activities of the materials were determined in a biochemical test reaction. Covalent grafting and building the complex onto the surface of the support were successful in all cases. It was found that in many instances the structures obtained and the coordinating groups substantially varied upon changing the conditions of the syntheses. All the covalently immobilised Ni(II)-complexes displayed enzyme-like activity. They also were active in the liquid-phase oxidation of cyclohexene, providing the epoxide with high selectivity.

Solventless mechanosynthesis of N-protected amino esters.

Mechanochemical derivatizations of N- or C-protected amino acids were performed in a ball mill under solvent-free conditions. A vibrational ball mill was used for the preparation of N-protected α- and β-amino esters starting from the corresponding N-unmasked precursors via a carbamoylation reaction in the presence of di-tert-butyl dicarbonate (Boc2O), benzyl chloroformate (Z-Cl) or 9-fluorenylmethoxycarbonyl chloroformate (Fmoc-Cl). A planetary ball mill proved to be more suitable for the synthesis of amino esters from N-protected amino acids via a one-pot activation/esterification reaction in the presence of various dialkyl dicarbonates or chloroformates. The spot-to-spot reactions were straightforward, leading to the final products in reduced reaction times with improved yields and simplified work-up procedures.

Synthesis, structural characterisation, and catalytic activity of Mn(II)–protected amino acid complexes covalently immobilised on chloropropylated silica gel

In this work the syntheses, structure, superoxide dismutase (SOD) activity and the catalytic use in the oxidative transformations of cyclohexene of covalently grafted Mn(II)–complexes formed with various C-protected amino acid (l-histidine, l-cysteine and l-cystine) ligands are presented. The structural features of the surface complexes were studied by EPR, X-ray absorption, and mid/far IR spectroscopies. The superoxide dismutase activities of the materials were determined in a biochemical test reaction. The obtained materials were used as catalysts for the oxidation of cyclohexene with peracetic acid in acetone. Covalent grafting and building the complex onto the surface of the chloropropylated silica gel were successful in all cases. It was found that in many instances the structures obtained and the coordinating groups substantially varied upon changing the conditions of the syntheses. All the covalently immobilised Mn(II)–complexes displayed superoxide dismutase activity and could catalyse the oxidation of cyclohexene.

Superoxide dismutase inspired Fe(III)−amino acid complexes covalently grafted onto chloropropylated silica gel – Syntheses, structural characterisation and catalytic activity

In this work the syntheses, structure and SOD activity of covalently grafted Fe(III)-complexes formed with various N- or C-protected amino acid ligands (L-histidine and L-tyrosine) inspired by the active site of the Fe–SOD enzyme are presented. Chloropropylated silica gel was used as support to mimic the proteomic skeleton of the enzyme. Anchored complexes having uniform amino acids as well as their two-component mixtures have been prepared. The products were characterised by mid and far IR and Raman spectroscopies. SOD activities of the substances were determined via the Beauchamp–Fridovich test reaction. It was found that the preparation of covalently anchored Fe(III)−amino acid complexes was successful in many cases. The structures of the anchored complexes and the coordinating groups varied upon changing the conditions of the syntheses. All the covalently immobilised complexes displayed (in some instances appreciable) SOD activity.

Ni-S(uper)O(xide)D(ismutase) Inspired Ni(II)-Amino Acid Complexes Covalently Grafted onto Merrifield’s Resin - Synthesis, Structure and Catalytic Activity

In this work the syntheses of covalently grafted Ni(II)-complexes formed with various N- or C-protected amino acid ligands (L-histidine, L-tyrosine, L-cysteine and L-cystine) inspired by the active site of the Ni-SOD enzyme are presented. Merrifield’s resin was used as support to mimic the proteomic skeleton of the enzyme. Conditions of the syntheses were altered and the structural features of the substances obtained were studied by infrared spectroscopy. It was found that the preparation of covalently anchored Ni(II)−amino acid complexes was successful in all cases. In many cases the structures of the anchored complexes and the coordinating groups substantially varied upon changing the conditions of the syntheses. The obtained materials were studied by energy dispersive X-ray fluorescence coupled to scanning electron microscope (SEM−EDX). All the covalently anchored materials displayed superoxide dismutase (SOD) activity and some proved to be exceptionally efficient in the biochemical test reaction.

Synthesis, Structure, and Glutathione Peroxidase‐Like Activity of Amino Acid Containing Ebselen Analogues and Diaryl Diselenides

The synthesis of some ebselen analogues and diaryl diselenides, which have amino acid functions as an intramolecularly coordinating group (Se···O) has been achieved by the DCC coupling procedure. The reaction of 2,2'-diselanediylbis(5-tert-butylisophthalic acid) or the activated ester tetrakis(2,5-dioxopyrrolidin-1-yl) 2,2'-diselanediylbis(5-tert-butylisophthalate) with different C-protected amino acids (Gly, L-Phe, L-Ala, and L-Trp) afforded the corresponding ebselen analogues. The used precursor diselenides have been found to undergo facile intramolecular cyclization during the amide bond formation reaction. In contrast, the DCC coupling of 2,2'-diselanediyldibenzoic acid with C-protected amino acids (Gly, L/D-Ala and L-Phe) affords the corresponding amide derivatives and not the ebselen analogues. Some of the representative compounds have been structurally characterized by single-crystal X-ray crystallography. The glutathione peroxidase (GPx)-like activities of the ebselen analogues and the diaryl diselenides have been evaluated by using the coupled reductase assay method. Intramolecularly stabilized ebselen analogues show slightly higher maximal velocity (V(max)) than ebselen. However, they do not show any GPx-like activity at low GSH concentrations at which ebselen and related diselenides are active. This could be attributed to the peroxide-mediated intramolecular cyclization of the corresponding selenenyl sulfide and diaryl diselenide intermediates generated during the catalytic cycle. Interestingly, the diaryl diselenides with alanine (L,L or D,D) amide moieties showed excellent catalytic efficiency (k(cat)/K(M)) with low K(M) values in comparison to the other compounds.

Synthesis, Gastroprotective Effect and Cytotoxicity of New Amino Acid Diterpene Monoamides and Diamides

Following our studies on the gastroprotective effect and cytotoxicity of terpene derivatives, new amides were prepared from the diterpene 8(17)-labden-15,19-dioic acid (junicedric acid) and its 8(9)-en isomer with C-protected amino acids (amino acid esters). The new compounds were evaluated for their gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice, as well as for cytotoxicity using the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma cells (AGS) and liver hepatocellular carcinoma (Hep G2). A dose-response experiment showed that at 25 mg/kg the C-15 leucyl and C-15,19-dileucylester amides of junicedric acid reduced gastric lesions by about 65.6 and 49.6%, respectively, with an effect comparable to lansoprazole at 20 mg/kg (79.3% lesion reduction). The comparison of the gastroprotective effect of 18 new amino acid ester amides was carried out at a single oral dose of 25 mg/kg. Several compounds presented a strong gastroprotective effect, reducing gastric lesions in the 70.9-87.8% range. The diprolyl derivative of junicedric acid, the most active product of this study (87.8% lesion reduction at 25 mg/kg) presented a cytotoxicity value comparable with that of the reference compound lansoprazole. The structure-activity relationships are discussed.

Gastroprotective Effect and Cytotoxicity of Labdeneamides with Amino Acids

Semisynthetic aromatic amides from ARAUCARIA ARAUCANA diterpene acids have been shown to display a relevant gastroprotective effect with low cytotoxicity. The aim of this work was to assess the gastroprotective effect of amino acid amides from imbricatolic acid and its 8(9)-en isomer in the ethanol/HCl-induced gastric lesions model in mice as well as to determine the cytotoxicity of the obtained compounds on the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma (AGS), and liver hepatocellular carcinoma (Hep G2). The diterpenes 15-acetoxyimbricatolic acid, its 8(9)-en isomer, 15-hydroxyimbricatolic acid, and the 8(9)-en derivative, bearing a COOH function at C-19, were used as starting compounds. New amides with C-protected amino acids were prepared. The study reports the effect of a single oral administration of either compound 50 min before the induction of gastric lesions by ethanol/HCl. Some 20 amino acid monoamides were obtained. Dose-response experiments on the glycyl derivatives showed that at a single oral dose of 100 mg/kg, the compounds presented an effect comparable to the reference drug lansoprazole at 20 mg/kg and at 50 mg/kg reduced gastric lesions by about 50%. All derivatives obtained in amounts > 30 mg were compared at a single oral dose of 50 mg/kg. The best gastroprotective effect was observed for the exomethylene derivatives bearing a valine residue at C-19 either with an acetoxy or free hydroxy group at C-15. The tryptophanyl derivative from the acetate belonging to the 8,9-en series presented selective cytotoxicity against hepatocytes. The glycyl amide of 15-acetoxyimbricatolic acid was the most cytotoxic and less selective compound with IC₅₀ values between 47 and 103 µM for the studied cell lines. This is the first report on the obtention of semisynthetic amino acid amides from labdane diterpenes.

A new approach towards peptidosulfonamides: synthesis of potential inhibitors of bacterial peptidoglycan biosynthesis enzymes MurD and MurE

Peptidosulfonamides are an emerging group of peptidomimetics with a variety of applications in medicinal chemistry. We present a novel approach to the synthesis of peptidosulfonamides, and apply it to a series of new potential inhibitors of the bacterial peptidoglycan biosynthesis enzymes MurD and MurE. The synthesis was conducted via N-phthalimido β-aminoethanesulfonyl chlorides, which are new building blocks for the synthesis of peptidosulfonamides. In the most crucial step, sulfonic acids or their sodium salts were converted into the corresponding sulfonyl chlorides using an excess of either SOCl 2 or SOCl 2/DMF, and then coupled to the C-protected amino acid. None of the compounds significantly inhibited MurD, however, some inhibited MurE; one had an IC 50 below 200 μM, which constitutes a promising starting point for further development. Molecular modelling simulations were performed on two analogues to investigate the absence of inhibitory activity of the sulfonamide compounds on MurD.

Synthesis of cinnamoyl and hydroxycinnamoyl amino acid conjugates and evaluation of their antioxidant activity

Fifteen amides of cinnamic, ferulic and sinapic acids with natural and unnatural C-protected amino acids have been synthesized. The amides (E)-N-(feruloyl)-L-tyrosine methyl ester (10), (E)-N-(feruloyl)-L-phenylalanine t-butyl ester (11), (E)-N-(sinapoyl)-L-tyrosine methyl ester (13) and (E)-N-(sinapoyl)-L-phenylalanine t-butyl ester (15) with a free carboxyl group of amino acids have been found in nature. The rest of the compounds are unknown. The hydroxycinnamoyl amino acid conjugates have been studied for their antioxidant activity (AOA) in bulk phase lipid autoxidation. The highest AOA has been found for the compounds 11 and 15, which contain the same phenylalanine moiety.

Highly efficient peptide bond formation to functionalized Wells-Dawson-type polyoxotungstates.

Making derivatives of organic side chains on polyoxometalates is an important prerequisite for their application in biology. Compounds α1- and α2-[P2W17O61{Sn(CH2)2CO2H}]7− (depicted) were prepared for the first time and coupled with alcohols and amines, including C-protected amino acids. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2003/z51346_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Synthesis of α,α-Disubstituted β-Amino Esters and Peptide Derivatives

The synthesis of a,a-disubstituted β-amino esters and peptide derivatives from readily available 4-spiro-β-lactams 1 is described. The geminally disubstituted β-amino esters are obtained from the N-Boc spiro β-lactams 2 by treatment with potassium cyanide in methanol. Alternatively, the use of spiro β-lactams 2 as acylating agents of the amino group of C-protected amino acids, allowed its direct incorporation into a peptidic chain.

A novel kinetically-controlled peptide synthesis—Dramatic increase of chemical yield with retention of chiral integrity

Peptide synthesis empolying the highly selective reaction of isobutyl chloroformate at the carboxyl group of the N-protected amino acid, almost to the exclusion of the amino group of the C-protected amino acid, is described. This one-stage, kinetically-controlled strategy remarkably affords peptides with excellent optical purity in high chemical yields.

Multi-component reactions 13: Synthesis of γ-lactams as part of a multiring system via Ugi-4-centre-3-component reaction

Preparation of γ-lactams 2a-h and 4a-h as part of a bi-or tri-cycle system in a one-pot Ugi-4-centre-3-component reaction (U-4C-3CR). A 3-keto or aldo acid was used as bifunctional educt. The application of C-protected amino acids as amine components enables an intramolecular condensation forming 2,6-piperazinediones 5a-h, connected to the γ-lactam system (1,4-diazabicyclo[4.3.0]nonane-3,5,9-triones).

A protection scheme for the preparation of acid chlorides of serine and threonine

N-acetyl oxazolone derivatives of serine and threonine are readily converted into reactive acid chlorides that condense efficiently with various C-protected aminoacids, even poorly nucleophilic ones.

A Protection Scheme for the Preparation of Acid Chlorides of Serine and Threonine

N-acetyl oxazolone derivatives of serine and threonine are readily converted into reactive acid chlorides that condense efficiently with various C-protected aminoacids, even poorly nucleophilic ones.